1. Field of the Invention
This invention relates generally to screening tests for gastrointestinal disease, and more particularly concerns a method and system for enhancing yield and improving patient comfort in production and collection of exfoliated cells from the gastrointestinal tract of a patient for chemical and biologic testing.
2. Description of Related Art
Standard testing procedures for cancer of the gut commonly entail either direct endoscopic visualization of the hollow viscera through which food passes in sequence, i.e., the pharynx, esophagus, stomach, small intestines, large intestine, and rectum, or contrast x-ray visualization of the lumen for abnormalities in the wall of the gut.
Screening tests are also known for detecting chemical markers, such as hemoglobin, ras DNA oncogenes and carcinoembryonic antigen (CEA), each of which is independently associated with gastrointestinal cancer. These screening tests typically involve either collecting formed feces and applying a sample of the collected stool to a test medium containing an indicator for the presence of the chemical marker associated with gastrointestinal cancer, or administering a laxative purge to the patient, collecting a watery fecal sample, and applying the watery fecal sample to a test medium containing an indicator. Typically when a laxative purge is employed, either the first or second watery post-purge bowel movement is collected following administration of the purge. However, conventional tests for chemical markers are commonly subject to false negatives and/or false positives, which can severely interfere with proper diagnosis and care for a patient.
It is thus apparent that there is a need for a test that is more reliable than chemical marker screening. It would be desirable to provide a screening method and system based on analysis of cells exfoliated from the tissues lining the gut. Conventionally, recovery of material from the gut suitable for cellular analysis was performed with either enemas or surgical methods requiring tubes or endoscopes to be passed into the area being investigated, which are invasive, uncomfortable for the patient, and expensive. Analysis of spontaneously passed stools for cellular parameters such as morphology or nucleic acid sequences is limited by the conditions existing in the gut, which cause rapid destruction of exfoliated cells, and conventional techniques do not adequately provide cells that are sufficiently preserved to be useful for cell based analysis.
It has been demonstrated that malignant cells can be reliably detected in bowel movements induced by oral administration of a balanced electrolyte lavage solution containing polyethylene glycol. The cells collected from the induced bowel movements were stained according to standard methods, and malignant cells were identified in the stained preparations in all patients with cancer. However, it was found that specimens were stable for only a few hours, with prolonged storage prior to processing damaging diagnostic accuracy, and that the test procedure could only detect colorectal cancer. In addition, processing of samples required trained technicians, with fixation and filtration procedures being required in the laboratory after specimen transport.
There is thus a need for a method and system for producing and collecting lavage induced stool (LIS) samples containing cells exfoliated from throughout the gut in sufficient numbers and free of interfering substances such as formed fecal particles for chemical assays and biologic assays for nucleic acid sequence information, for medical diagnosis of cancer of the colon, rectum, stomach and esophagus and other medical conditions using standard cytopathology methods. It would also be desirable to provide a method for producing and collecting LIS samples containing higher numbers of exfoliated cells, and with improved preservation of morphological and chemical properties than has been achievable in the prior art. It would be desirable to provide a kit for carrying out the method of the invention, for use by patients without assistance to produce a LIS sample suitable for analysis. It would also be desirable to provide a collection kit that employs a sequence of ingested substances to produce preserved cells for medical diagnosis, allowing cytologic analysis of the LIS for diagnosis of foregut and hindgut disease, and providing better palatability and comfort for patients than previous lavage stool cytology methods. The present invention meets these needs.
Briefly, and in general terms, the present invention provides for a method for producing LIS samples containing cells exfoliated from throughout the gut in sufficient numbers and free of interfering substances such as formed fecal particles for chemical assays and biologic assays for nucleic acid sequence information, and medical diagnosis. From such LIS samples, cancer of the colon, rectum, stomach and esophagus and other medical conditions can be readily diagnosed using standard cytopathology methods. The method allows analysis of cells exfoliated from throughout the gastrointestinal tract, and produces samples with higher numbers of cells with better preservation of morphological and chemical properties than has been achievable heretofore. The method of the invention is also useful for mechanical cleansing of the gut and bowel compatible for preparation of patients for surgical procedures such as fiberoptic endoscopy.
The invention also provides for a kit for use by patients without assistance to produce a LIS sample suitable for analysis. The collection kit of the invention employs a sequence of ingested substances to produce preserved cells for medical diagnosis, allowing cytologic analysis of the LIS for diagnosis of foregut and hindgut disease. Home collection and the use of fixatives make the test kit convenient and the cost of the overall test procedure relatively low. Compared to stool produced by ingestion of PEG lavage solution, stools produced by the kit procedure have more and purer exfoliated cells improving diagnostic accuracy. The specific sequence of substances administered and kit procedures provide better palatability and comfort than previous lavage stool cytology methods. The kit permits the low cost, non-invasive, and accurate detection of common gastrointestinal malignancies. The kit allows a subject to perform the collection procedure at home safely, conveniently, and with greater comfort. The preserved specimen can be stored several days without damaging its diagnostic potential, and can be safely transported by carrier or post. Home administration and prolonged specimen stability greatly increase the practicality and cost effectiveness of the test procedure. The combination of ingested substances leads to improved purity and yield of exfoliated cells, and allows better diagnosis of disease of the stomach and esophagus, in addition to allowing detection of colorectal conditions.
The invention accordingly provides for a method for producing and collecting lavage induced stools for chemical and biological tests of cells exfoliated from a patient""s digestive tract. The steps of the method generally comprise orally administering a preliminary cathartic lavage to cleanse a patient""s digestive tract; collecting at least one stool induced by the preliminary cathartic lavage; and administering a final cathartic lavage to exfoliate and preserve cells from a patient""s digestive tract. In one currently preferred embodiment, the step of orally administering a preliminary cathartic lavage comprises orally administering approximately 500 ml of a mannitol solution and collecting the patient""s stool, and repeating this step until the patient""s stool is substantially free of sediment or formed stool particles. In another currently preferred aspect of the invention, the step of orally administering a preliminary cathartic lavage can further comprise orally administering at least one timed release capsule containing medication that increases exfoliation of cells from the lining of the gut after completing preliminary lavage administration, and waiting a predetermined time interval, such as approximately two hours, before the next step. This preliminary phase can additionally also comprise collecting a first solid stool and a second liquid stool for further analysis. The patient is allowed an electrolyte beverage ad lib during this stage until feces collection is finished. In a currently preferred embodiment, the step of administering a final cathartic lavage comprises administering approximately 250 mls of a final lavage solution every 15 minutes until a the patient""s stool is substantially clear. The method of the invention can also comprise the step of processing of the collected LIS specimen for return for analysis, and generally comprises transferring approximately 50 to 100 ml of the LIS specimen collected in a toilet pan into a filtration apparatus. The LIS specimen is then transferred via the filtration apparatus into a specimen container having a fixative for preserving the LIS specimen. After the specimen container is filled to a predetermined level, the safety lid is secured and the sealed container is placed in a mailing carton meeting U.S. biohazard regulations for transport via courier or post to a laboratory for analysis.
The invention thus also provides for a specimen container and filter device that are specially designed to promote safe and convenient processing of the sample, with a special seal inside the specimen container to prevent splashing or leakage of fixative during the transfer from the filter device.
In another aspect, the invention provides for a test kit for producing and collecting lavage induced stool for chemical and biological tests of cells exfoliated from a patient""s digestive tract. The invention is a kit to be used at home for collection of a stool sample induced by the ingestion of a sequence of beverages, medication and medicated foods. The kit components and procedures produce stool specimens with preserved exfoliated gastrointestinal cells suitable for medical diagnosis based on histopathologic, biologic, and chemical tests. Cells produced from the kit procedures and components are derived from both the foregut and hindgut allowing diagnosis of both esophageal and rectal cancer as well as other diseases. The kit components and procedures are designed to make the ingested substances palatable and the collection of stool samples convenient and safe.
The test kit can comprise instructional materials including color pictures of LIS samples in collection containers for comparison with collected samples while carrying out the method of the invention; disposable collection apparatus, such as beverage containers, collection pans that fit standard toilet bowl dimensions, collection syringes, a filtration device, and a LIS specimen container with fixative (such as 10% buffered formalin, for example) to collect solid and liquid bowel motions generated by the test procedure, as well as a mailing carton, labels and gloves.
The test kit of the invention also preferably contains an advanced formulation of a beverage or beverages and/or powdered chemicals for reconstitution as beverages or medication, medications, foods, and medicated foods. In one preferred aspect of the kit, the powdered chemicals include sufficient powder to prepare approximately 6 liters of a sweet tasting balanced electrolyte and salt solution similar to sports drinks such as Gatorade, by reconstitution with water. The drink may be modified with additives such as hormones, proteolytic enzymes, calcium chelating agents such as EDTA, mucolytics, bile salts such as chenodeoxycholate, and buffers such as bicarbonate salts and/or HEPES, which induce increased exfoliation and/or preservation of cells. In another preferred aspect of the invention, the kit can also include hard candies based on sorbitol and/or dextrose, to ameliorate the flavor of a final lavage solution. These candies may contain EDTA or other drugs which promote exfoliation of gut mucosa cells. The kit also includes a cathartic medication, such as 250 ml of magnesium citrate, to induce the production of a formed stool. The kit further includes sufficient powder to prepare up to one liter of a preliminary lavage solution, and may, for example, contain buffered mannitol. The preliminary lavage solution may also contain additives such as hormones, proteolytic enzymes, calcium chelating agents such as EDTA, mucolytics, bile salts such as chenodeoxycholate, and buffers such as bicarbonate salts and/or HEPES, to induce increased exfoliation and/or preservation of cells. The kit further contains sufficient powder to prepare up to 4 liters of a final lavage solution containing buffers, inorganic salts, polyethylene glycol, and additives such as hormones, proteolytic enzymes, calcium chelating agents such as EDTA, mucolytics, bile salts such as chenodeoxycholate, and buffers such as bicarbonate salts and/or HEPES, to induce increased exfoliation and/or preservation of cells. The kit may additionally contain time release capsules containing substances such as hormones, drugs, buffer salts, proteases, EDTA, or bile salts, which when released into the gut at the proper time in the test procedure improve the yield or preservation of cells recovered in the LIS.
These and other aspects and advantages of the invention will become apparent from the following detailed description and the accompanying drawings, which illustrate by way of example the features of the invention.